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===Inefficacy of metformin===
===Inefficacy of metformin===
Previously, metformin was recommended treatment for anovulation.
⚫
Previously, metformin was recommended treatment for anovulation. However, in the largest trial to date, comparing clomiphene with metformin, clomiphene was more effective than metformin alone.<ref>{{cite journal |author=Legro RS, Barnhart HX, Schlaff WD |title=Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome |journal=N Engl J Med |volume=356 |issue=6 |pages=551–66 |year=2007 |pmid=17287476 |doi=10.1056/NEJMoa063971}}</ref> In this trial, 626 women were randomized to three groups: metformin alone, clomiphene alone, or both. The live-birth rates following 6 months of treatment were 7.2% (metformin), 22.5% (clomiphene), and 26.8% (both). The major complication of clomiphene was multiple pregnancy, affecting 0%, 6% and 3.1% of women respectively. The overall success rates for live birth remained disappointing, even in women receiving combined therapy, but it is important to consider that the women in this trial had already been attempting to conceive for an average of 3.5 years, and over half had received previous treatment for infertility. Thus, these were women with significant fertility problems, and the live-birth rates are probably not representative of the typical PCOS woman. Following this study, the ESHRE/ASRM-sponsored Consensus workshop does not recommend metformin for ovulation stimulation.<ref name="pmid18243179">{{cite journal |author=Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group |title=Consensus on infertility treatment related to polycystic ovary syndrome |journal=Fertil. Steril. |volume=89 |issue=3 |pages=505–22 |year=2008 |month=March |pmid=18243179 |doi=10.1016/j.fertnstert.2007.09.041 |url=}}</ref> Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.<ref>{{cite journal |author=Johnson NP, Stewart AW, Falkiner J, ''et al.'' |title=PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene |journal=Hum Reprod |volume= 25|issue= 7|pages= 1675–83|year=2010 |month=April |pmid=20435692 |doi=10.1093/humrep/deq100 |url=}}</ref>


A [[systematic review]] and [[meta-analysis]] in 2012<ref name=Misso2012/> came to the conclusion that there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI less than 32 kg/m<sup>2</sup>.<ref name=Misso2012>{{cite doi|10.1093/humupd/dms036}}</ref> It emphasized that a lack of superiority of one treatment is not evidence for equivalence.<ref name=Misso2012/>
A [[systematic review]] and [[meta-analysis]] in 2012<ref name=Misso2012/> came to the conclusion that there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI less than 32 kg/m<sup>2</sup>.<ref name=Misso2012>{{cite doi|10.1093/humupd/dms036}}</ref> It emphasized that a lack of superiority of one treatment is not evidence for equivalence.<ref name=Misso2012/>


Another review in 2012<ref name=Tang2012/> came to the conclusion that metformin improves [[pregnancy rate]]s in women with PCOS when compared with placebo, and in addition to clomiphene compared with clomiphene alone, but not when compared directly with clomiphene. Also, however, it came to the conclusion that metformin does not improve [[live birth rate]]s whether it is used alone or in combination with clomiphene. It therefore concluded that the the benefit of metformin in the improvement of reproductive outcomes in women with PCOS appears limited.<ref name=Tang2012>{{cite doi|10.1093/humupd/dms040}}</ref>
Another review in 2012<ref name=Tang2012/> came to the conclusion that metformin improves [[pregnancy rate]]s in women with PCOS when compared with placebo, and in addition to clomiphene compared with clomiphene alone, but not when compared directly with clomiphene. Also, however, it came to the conclusion that metformin does not improve [[live birth rate]]s whether it is used alone or in combination with clomiphene. It therefore concluded that the the benefit of metformin in the improvement of reproductive outcomes in women with PCOS appears limited.<ref name=Tang2012>{{cite doi|10.1093/humupd/dms040}}</ref>

⚫
The ESHRE/ASRM-sponsored Consensus workshop does not recommend metformin for ovulation stimulation.<ref name="pmid18243179">{{cite journal |author=Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group |title=Consensus on infertility treatment related to polycystic ovary syndrome |journal=Fertil. Steril. |volume=89 |issue=3 |pages=505–22 |year=2008 |month=March |pmid=18243179 |doi=10.1016/j.fertnstert.2007.09.041 |url=}}</ref> Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.<ref>{{cite journal |author=Johnson NP, Stewart AW, Falkiner J, ''et al.'' |title=PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene |journal=Hum Reprod |volume= 25|issue= 7|pages= 1675–83|year=2010 |month=April |pmid=20435692 |doi=10.1093/humrep/deq100 |url=}}</ref>


==Prognosis==
==Prognosis==

Revision as of 18:21, 13 December 2012

Polycystic ovary disease (PCOS) is thought to be one of the leading causes of female infertility.[1][2][3][4] Polycystic ovary syndrome is the cause of more than 75% of cases of anovulatory infertility.[5]

Pathophysiology

Not all women with PCOS have difficulty becoming pregnant.[citation needed] For those who do, anovulation is a common cause. The mechanism of this anovulation is uncertain, but there is evidence of arrested antral follicle development, which, in turn, may be caused by abnormal interaction of insulin and luteinizing hormone (LH) on granulosa cells.[5]

Endocrine disruption may also directly decrease fertility, such as changed levels of gonadotropin-releasing hormone[6], gonadotropins (especially an increase in luteinizing hormone)[7][6], hyperandrogenemia[8] and hyperinsulinemia[8]. Gonadotropins are released by gonadotroph cells in pituary gland, and these cells appear to harbor insulin receptors, which are affected by too high insulin levels in body.[6] A reason that insulin sensitizers work in increasing fertility is that they lower total insulin levels in body as metabolic tissues regain sensitivity to the hormone. This will reduce the overstimulation of gonadotroph cells in pituitary.[6]

Diagnosis

PCOS usually causes infertility associated with anovulation, and therefore, the presence of ovulation indicates absence of infertility, although it does not rule out infertility by other causes.

Ovulation prediction

Ovulation may be predicted by the use of urine tests that detect the preovulatory LH surge, called ovulation predictor kits (OPKs). However, OPKs are not always accurate when testing on women with PCOS.[9] Charting of cervical mucus may also be used to predict ovulation, or certain fertility monitors (those that track urinary hormones or changes in saliva) may be used. Methods that predict ovulation may be used to time intercourse or insemination appropriately.

While not useful for predicting ovulation,[10] basal body temperatures may be used to confirm ovulation. Ovulation may also be confirmed by testing for serum progesterone in mid-luteal phase, approximately seven days after ovulation (if ovulation occurred on the average cycle day of fourteen, seven days later would be cycle day 21). A mid-luteal phase progesterone test may also be used to diagnose luteal phase defect. Methods that confirm ovulation may be used to evaluate the effectiveness of treatments to stimulate ovulation.

Management

Management of infertility in polycystic ovary syndrome includes lifestyle modification as well as assisted reproductive technology such as ovulation induction, oocyte release triggering and surgery.

Lifestyle modification

For overweight women with PCOS who are anovulatory, diet adjustments and weight loss are associated with resumption of spontaneous ovulation.

Ovulation induction

For those who after weightloss still are anovulatory or for anovulatory lean women, ovulation induction to reverse the anovulation is the principal treatment used to help infertility in PCOS. Clomiphene citrate is the main medication used for this purpose, and is the first-line treatment in subfertile anovulatory patients with PCOS.[11] Gonadotrophins such as follicle-stimulating hormone (FSH) are, in addition to surgery, second-line treatments.[11] Aromatase inhibitors show promising results.[11]

In vitro fertilization

For patients who do not respond to diet, lifestyle modification and clomiphene, in vitro fertilisation can be performed. This usually includes controlled ovarian hyperstimulation with FSH injections, and oocyte release triggering with human chorionic gonadotropin (hCG) or a GnRH agonist.

Surgery

Surgery can be attempted in case of inefficient result with medications for ovulation induction.[11] Though surgery is not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling" (puncture of 4-10 small follicles with electrocautery), which often results in either resumption of spontaneous ovulations or ovulations after adjuvant treatment with clomiphene or FSH.

Inefficacy of metformin

Previously, metformin was recommended treatment for anovulation.

A systematic review and meta-analysis in 2012[12] came to the conclusion that there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI less than 32 kg/m2.[12] It emphasized that a lack of superiority of one treatment is not evidence for equivalence.[12]

Another review in 2012[13] came to the conclusion that metformin improves pregnancy rates in women with PCOS when compared with placebo, and in addition to clomiphene compared with clomiphene alone, but not when compared directly with clomiphene. Also, however, it came to the conclusion that metformin does not improve live birth rates whether it is used alone or in combination with clomiphene. It therefore concluded that the the benefit of metformin in the improvement of reproductive outcomes in women with PCOS appears limited.[13]

The ESHRE/ASRM-sponsored Consensus workshop does not recommend metformin for ovulation stimulation.[14] Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.[15]

Prognosis

PCOS causes an increased time to pregnancy but the eventual family size is not necessarily reduced.[11] The frequency of miscarriage does not appear to be increased.[11]

References

  1. ^ Goldenberg N, Glueck C (2008). "Medical therapy in women with polycystic ovary syndrome before and during pregnancy and lactation". Minerva Ginecol. 60 (1): 63–75. PMID 18277353.
  2. ^ Boomsma CM, Fauser BC, Macklon NS (2008). "Pregnancy complications in women with polycystic ovary syndrome". Semin. Reprod. Med. 26 (1): 72–84. doi:10.1055/s-2007-992927. PMID 18181085.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Palacio JR et,al.The presence of antibodies to oxidative modified proteins in serum from polycystic ovary syndrome patients Clin Exp Immunol. 2006 May;144(2):217-22.PMID 16634794
  4. ^ Azziz R. et.al.The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004 Jun;89(6):2745-9. PMID 15181052
  5. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17185789, please use {{cite journal}} with |pmid=17185789 instead.
  6. ^ a b c d Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.cmet.2010.06.010, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.cmet.2010.06.010 instead.
  7. ^ Deepak A. Rao; Le, Tao; Bhushan, Vikas (2007). First Aid for the USMLE Step 1 2008 (First Aid for the Usmle Step 1). McGraw-Hill Medical. ISBN 0-07-149868-0.{{cite book}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/humupd/dmq032, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/humupd/dmq032 instead.
  9. ^ "Question about opks with pcos". Retrieved 7 May 2010.
  10. ^ Guermandi E, Vegetti W, Bianchi MM, Uglietti A, Ragni G, Crosignani P (2001). "Reliability of ovulation tests in infertile women" (– Scholar search). Obstet Gynecol. 97 (1): 92–6. doi:10.1016/S0029-7844(00)01083-8. PMID 11152915. {{cite journal}}: External link in |format= (help)CS1 maint: multiple names: authors list (link) [dead link‍]
  11. ^ a b c d e f Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/humupd/dms019, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/humupd/dms019 instead.
  12. ^ a b c Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/humupd/dms036, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/humupd/dms036 instead.
  13. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/humupd/dms040, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/humupd/dms040 instead.
  14. ^ Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2008). "Consensus on infertility treatment related to polycystic ovary syndrome". Fertil. Steril. 89 (3): 505–22. doi:10.1016/j.fertnstert.2007.09.041. PMID 18243179. {{cite journal}}: Unknown parameter |month= ignored (help)
  15. ^ Johnson NP, Stewart AW, Falkiner J; et al. (2010). "PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene". Hum Reprod. 25 (7): 1675–83. doi:10.1093/humrep/deq100. PMID 20435692. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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